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© 1999 American Heart Association, Inc.
Original Contribution |
Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, II
Model Studies
From the Departments of Biomedical Engineering (R.L.W., J.R., S.J.) and Computer Science (R.L.W.) and Center for Computational Medicine and Biology (R.L.W., J.R., S.J.), The Johns Hopkins University School of Medicine and Whiting School of Engineering, and Section of Molecular and Cellular Cardiology (E.M., B.O.), Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Raimond L. Winslow, PhD, The Johns Hopkins University School of Medicine, Department of Biomedical Engineering, 411 Traylor Research Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail rwinslow{at}bme.jhu.edu
Abstract—Ca2+ transients measured in failing human ventricular myocytes exhibit reduced amplitude, slowed relaxation, and blunted frequency dependence. In the companion article (O'Rourke B, Kass DA, Tomaselli GF, Kääb S, Tunin R, Marbán E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, I: experimental studies. Circ Res. 1999;84:562–570), O'Rourke et al show that Ca2+ transients recorded in myocytes isolated from canine hearts subjected to the tachycardia pacing protocol exhibit similar responses. Analyses of protein levels in these failing hearts reveal that both SR Ca2+ ATPase and phospholamban are decreased on average by 28% and that Na+/Ca2+ exchanger (NCX) protein is increased on average by 104%. In this article, we present a model of the canine midmyocardial ventricular action potential and Ca2+ transient. The model is used to estimate the degree of functional upregulation and downregulation of NCX and SR Ca2+ ATPase in heart failure using data obtained from 2 different experimental protocols. Model estimates of average SR Ca2+ ATPase functional downregulation obtained using these experimental protocols are 49% and 62%. Model estimates of average NCX functional upregulation range are 38% and 75%. Simulation of voltage-clamp Ca2+ transients indicates that such changes are sufficient to account for the reduced amplitude, altered shape, and slowed relaxation of Ca2+ transients in the failing canine heart. Model analyses also suggest that altered expression of Ca2+ handling proteins plays a significant role in prolongation of action potential duration in failing canine myocytes.
Key Words: excitation-contraction coupling • heart failure • midmyocardial ventricular action potential • Ca2+ transient
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